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Lyxumia Subcutaneous Injection 300 Μg [Non-Proprietary Name] Lixisenatide (JAN*) [Name of Applicant] Sanofi K.K

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Lyxumia Subcutaneous Injection 300 Μg [Non-Proprietary Name] Lixisenatide (JAN*) [Name of Applicant] Sanofi K.K Report on the Deliberation Results May 31, 2013 Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau Ministry of Health, Labour and Welfare [Brand name] Lyxumia Subcutaneous Injection 300 μg [Non-proprietary name] Lixisenatide (JAN*) [Name of applicant] Sanofi K.K. [Date of application] June 11, 2012 [Results of deliberation] In the meeting held on May 24, 2013, the First Committee on New Drugs concluded that the product may be approved and that this result should be reported to the Pharmaceutical Affairs Department of the Pharmaceutical Affairs and Food Sanitation Council. The re-examination period for the product is 8 years, and the drug substance and the drug product are both classified as powerful drugs and the product is not classified as a biological product or a specified biological product. The proposed Japanese brand name should be changed for ensuring medical safety. *Japanese Accepted Name (modified INN) This English version of the Japanese review report is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. The PMDA will not be responsible for any consequence resulting from the use of this English version. Review Report May 7, 2013 Pharmaceuticals and Medical Devices Agency The results of a regulatory review conducted by the Pharmaceuticals and Medical Devices Agency on the following pharmaceutical product submitted for registration are as follows. [Brand name] Lyxumia Subcutaneous Injection 300 μg [Non-proprietary name] Lixisenatide [Name of applicant] Sanofi K.K. [Date of application] June 11, 2012 [Dosage form/Strength] Solution for injection containing 300 μg of Lixisenatide per cartridge (3 mL) [Application classification] Prescription drug (1) Drug with a new active ingredient [Chemical structure] His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Le u-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH2 Molecular formula: C215H347N61O65S Molecular weight: 4858.49 Chemical name: Lixisenatide is a synthetic analog of exendin-4 in which Pro residue at position 38 is removed and 6 Lys residues are attached at the C-terminal. Lixisenatide is a peptide consisting of 44 amino acid residues. [Items warranting special mention] None [Reviewing office] Office of New Drug I This English version of the Japanese review report is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. The PMDA will not be responsible for any consequence resulting from the use of this English version. Review Results May 7, 2013 [Brand name] Lyxumia Subcutaneous Injection 300 μg [Non-proprietary name] Lixisenatide [Name of applicant] Sanofi K.K. [Date of application] June 11, 2012 [Results of review] Based on the submitted data, the efficacy of the product in patients with type 2 diabetes mellitus has been demonstrated and its safety is acceptable in view of its observed benefits. The occurrence of hypoglycaemia, gastrointestinal disorders, pancreatitis, and injection site reactions, the influence of antibody formation on safety and efficacy, effects on renal function, hypersensitivity reactions, cardiovascular risk, tumor development, safety in patients with renal or hepatic impairment and elderly patients (limited numbers of these patients were included in clinical studies), the safety and efficacy of the product in combination with a sulfonylurea and high-dose metformin, and the long-term safety and efficacy of the product in combination with basal insulin, etc. need to be further investigated via post-marketing surveillance. As a result of its regulatory review, the Pharmaceuticals and Medical Devices Agency has concluded that the product may be approved for the following indication and dosage and administration. [Indication] Type 2 diabetes mellitus: Lyxumia should be used only when either of the following does not provide adequate glycaemic control: (a) diet and exercise plus sulfonylureas (with or without biguanides) or (b) diet and exercise plus soluble prolonged-acting or intermediate-acting insulin (with or without sulfonylureas). [Dosage and administration] The usual adult dosage is 20 μg of Lixisenatide subcutaneously injected once daily prior to breakfast. Lixisenatide should be initiated at 10 μg once daily, which is increased to 15 μg once daily after at least 1 week and then to 20 μg once daily after at least 1 week. The dosage may be adjusted according to the patient’s condition. The daily dose should not exceed 20 μg. 3 Review Report (1) March 22, 2013 I. Product Submitted for Registration [Brand name] Lyxumia Subcutaneous Injection 300 μg [Non-proprietary name] Lixisenatide [Name of applicant] Sanofi-Aventis K.K. (a predecessor of Sanofi K.K.) [Date of application] June 11, 2012 [Dosage form/Strength] Solution for injection containing 300 μg of Lixisenatide per cartridge (3 mL). [Proposed indication] Type 2 diabetes mellitus: Lyxumia should be used only when any of the following therapies does not provide adequate glycaemic control: (a) ************************, (b) diet and exercise plus sulfonylureas (with or without biguanides), or (c) diet and exercise plus soluble prolonged-acting or intermediate-acting insulin (with or without sulfonylureas). [Proposed dosage and administration] The usual adult dosage is 20 μg of Lixisenatide subcutaneously injected once daily prior to breakfast or evening meal. Lixisenatide should be initiated at 10 μg once daily, which is increased to 15 μg once daily after at least 1 week and then to 20 μg once daily after at least 1 week. The dosage may be adjusted according to the patient’s condition. The daily dose should not exceed 20 μg. II. Summary of the Submitted Data and Outline of Review by Pharmaceuticals and Medical Devices Agency A summary of the data submitted in the application and an outline of the review by the Pharmaceuticals and Medical Devices Agency (PMDA) are as shown below. 1. Origin or history of discovery and usage conditions in foreign countries etc. The proposed product is a solution for injection containing Lixisenatide (lixisenatide) as the active ingredient, which is a glucagon-like peptide-1 (GLP-1) receptor agonist discovered by Zealand Pharma A/S and subsequently developed by Sanofi-Aventis K.K. (a predecessor of Sanofi K.K.), which is the applicant. GLP-1 is secreted from the gastrointestinal tract in response to ingestion of a meal, and plays an important role in postprandial glucose regulation by facilitating insulin release and suppressing glucagon secretion from the pancreas. However, GLP-1 is rapidly degraded and inactivated by dipeptidyl peptidase-4 (DPP-4) which is distributed throughout the body and has a short half-life of approximately 90 to 120 seconds. The product is a GLP-1 receptor agonist with structural similarities to exendin-4,1 which is resistant to enzymatic cleavage by DPP-4, and stimulates insulin release by binding to the GLP-1 receptor and thus exerts a glucose-lowering effect. 1 A peptide consisting of 39 amino acids, isolated from saliva of a kind of lizard (Heloderma suspectum) 4 The applicant has submitted a new drug application for Lyxumia as efficacy and safety have been confirmed for Lyxumia when used in combination with sulfonylureas (with or without biguanides) and with basal insulin (with or without sulfonylureas) for the treatment of type 2 diabetes mellitus. The applicant removed ************************ as the proposed indication after the submission of the application. As of March 2013, the product has been approved in Europe and is under review in the US. As GLP-1 receptor agonists, liraglutide (genetical recombination) and exenatide have already been approved in Japan. 2. Data relating to quality 2.A Summary of the submitted data 2.A.(1) Drug substance 2.A.(1).1) Characterization The drug substance is an amorphous, white powder. The physicochemical properties of the drug substance, including general properties (appearance, solubility, melting point, hygroscopicity [************ **********************], isoelectric point, biological activity, pH, and crystallographic property [X-ray powder diffraction]) have been determined. Its chemical structure has been elucidated by mass spectrometry (electrospray ionization [ESI]), peptide mapping (reversed-phase liquid chromatography [HPLC] and liquid chromatography/mass spectrometry [LC-MS]), amino acid compositional analysis, amino acid sequencing (Edman sequencing technique), infrared spectroscopy (IR), ultraviolet spectroscopy (UV), circular dichroism (CD) spectroscopy, nuclear magnetic resonance spectroscopy (1H, 13C, 15N, NOESY), and fluorescence spectroscopy. 2.A.(1).2) Manufacturing process Starting materials used for synthesis of drug substance are ******************, ******************, ******************, ******************, ******************, ***********************, ***********, ***********, ************, *******************, *************, **************, ************** or *****************, ******************, ******************, ******************, *************, ********************** and *******************. ******************************, *******************, ******************* and *** ************ have been defined as critical steps. As critical intermediates, ***************, ********************************
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